6-hydroxy-indazole derivatives for treating glaucoma

ABSTRACT

Substituted 1-(α-alkyl-ethylamino)-1H-indazol-6-ols useful for lowering and controlling IOP and treating glaucoma are disclosed

This application claims priority from PCT/US00/31247 filed on Nov. 14,2000, and U.S. Ser. No. 60/190,380, filed on Mar. 17, 2000.

The present invention is directed to novel substituted1-(α-alkyl-ethylamino)-1H-indazol-6-ols. These novel compounds areuseful for lowering and controlling normal or elevated intraocularpressure (IOP) and treating glaucoma.

BACKGROUND OF THE INVENTION

The disease state referred to as glaucoma is characterized by apermanent loss of visual function due to irreversible damage to theoptic nerve. The several morphologically or functionally distinct typesof glaucoma are typically characterized by elevated IOP, which isconsidered to be causally related to the pathological course of thedisease. Ocular hypertension is a condition wherein intraocular pressureis elevated but no apparent loss of visual function has occurred; suchpatients are considered to be a high risk for the eventual developmentof the visual loss associated with glaucoma. Some patients withglaucomatous field loss have relatively low intraocular pressure. Theseso called normotension or low tension glaucoma patients can also benefitfrom agents that lower and control IOP. If glaucoma or ocularhypertension is detected early and treated promptly with medicationsthat effectively reduce elevated intraocular pressure, loss of visualfunction or its progressive deterioration can generally be ameliorated.Drug therapies that have proven to be effective for the reduction ofintraocular pressure include both agents that decrease aqueous humorproduction and agents that increase the outflow facility. Such therapiesare in general administered by one of two possible routes, topically(direct application to the eye) or orally.

There are some individuals who do not respond well when treated withcertain existing glaucoma therapies. There is, therefore, a need forother topical therapeutic agents that control IOP.

It has been found that serotonergic compounds which possess agonistactivity at 5-HT₂ receptors effectively lower and control normal andelevated IOP and are useful for treating glaucoma, see commonly ownedco-pending application, PCT/US99/19888. Compounds that act as agonistsat 5-HT₂ receptors are well known and have shown a variety of utilities,primarily for disorders or conditions associated with the centralnervous system (CNS). U.S. Pat. No. 5,494,928 discloses certain2-(indol-1-yl)-ethylamine derivatives that are 5-HT_(2C) agonists forthe treatment of obsessive compulsive disorder and other CNS derivedpersonality disorders. U.S. Pat. No. 5,571,833 discloses tryptaminederivatives that are 5-HT₂ agonists for the treatment of portalhypertension and migraine. U.S. Pat. No. 5,874,477 discloses a methodfor treating malaria using 5-HT_(2A/2C) agonists. U.S. Pat. No.5,902,815 discloses the use of 5-HT_(2A) agonists to prevent adverseeffects of NMDA receptor hypofunction. Published International PatentApplication No. WO98/30548 discloses that selected1-ethylamino-1H-indazoles substituted at ring positions 4-, 5-, 6-, or7- have selective affinity for the 5-HT_(2C) receptor and thereby haveutility in the treatment of central nervous system diseases.International Patent Application Nos. WO00/12481 and WO00/17170 discloseyet other 1-ethylamino-1H-indazoles that have selective affinity for the5-HT_(2C) receptor and thereby have utility in the treatment ofdisorders of the central nervous system. Published International PatentApplication No. WO98/31354A2 discloses 5-HT_(2B) agonists for thetreatment of depression and other CNS conditions. WO00/35922 disclosescertain pyrazino[1,2-a]quinoxaline derivatives as 5-HT_(2C) agonists forthe treatment of obsessive-compulsive disorder, depression, eatingdisorders, and other disorders involving the CNS. Agonist response atthe 5-HT_(2A) receptor is reported to be the primary activityresponsible for hallucinogenic activity, with some lesser involvement ofthe 5-HT_(2C) receptor possible [Psychopharmacology, Vol. 121:357,1995].

The present invention is directed to novel substituted1-(α-alkyl-ethylamino)-1H-indazol-6-ols. It has been determined thatthese novel compounds have a high affinity for and function as agonistsat the serotonergic 5-HT₂ receptor, and are useful for lowering andcontrolling normal or elevated intraocular pressure (IOP) and treatingglaucoma. When a phenolic moiety is included in this substitution, e.g.a hydroxyl group at indazole ring position six, such compounds can beparticularly sensitive to oxidation reactions well known to occur withphenolic compounds in general, including hydroxytryptamines [J. Phys.Chem. 103, 8606 (1999), Chem. Res. Toxicol. 11, 639 (1998), J. Org.Chem. 52, 2817 (1987), J. Pharm. Sci. 77, 911 (1988)], which are ofparticular relevance to the present application. Protection of suchphenyls from oxidation can be accomplished by derivatization of the arylhydroxyl group to provide a suitable ester, carbamate, or carbonate.Though the ester, carbamate, or carbonate derivatives do not themselvespossess a high affinity for the above mentioned receptors, they do haveutility in the treatment of glaucoma since suitably protected phenolscan be cleaved in vivo either by chemical hydrolysis or through theaction of tissue esterases, thereby delivering the desired therapeuticagent, that is, the desired novel 6-hydroxy-indazole compounds of thepresent invention. The concept of utilizing such derivatized phenoliccompounds as chemical delivery agents is well known in the art [DrugsPharm. Sci. 53, 221 (1992), Pharm. Res., 168 (1984)].

SUMMARY OF THE INVENTION

The present invention is directed to new and known derivatives of1-(ethylamino)-1H-indazole that can be used to lower and control IOPassociated with normal-tension glaucoma, ocular hypertension, andglaucoma in warm-blooded animals, including man. The compounds areformulated in pharmaceutical compositions suitable for topical deliveryto the eye.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Compounds that are useful according to the present invention arerepresented by the following Formula I.

-   wherein R¹ to R⁴ are independently chosen from hydrogen, halogen,    C₁₋₆alkyl, trifluoromethyl, O—W, C₁₋₆alkylthio, C₁₋₆alkylsulfoxyl,    C₁₋₆alkylsulfonyl, or cyano;-   R⁵ can be hydrogen, C₁₋₆alkyl, or C₁₋₄alkoxy, halogen,    trifluoromethyl, cyano, NR¹⁰R¹¹;-   R⁶ and R⁷ are independently chosen from hydrogen, C₁₋₄alkyl or R⁶,    R⁷ and the carbon atom to which they are attached can form a    cyclopropyl ring, or furthermore, R⁷ and R⁸ together can be    (CH₂)_(m) to form a saturated heterocycle;-   R⁸ and R⁹ are independently chosen from hydrogen or C₁₋₄alkyl;-   R¹⁰ and R¹¹ are independently chosen from hydrogen or C₁₋₄alkyl, or    R¹⁰, R¹¹ and the nitrogen atom to which they are attached can form a    saturated heterocyclic ring selected from pyrrolidine, piperidine,    piperazine, or morpholine;-   R¹ to R⁴ cannot simultaneously be hydrogen;-   R⁶ and R⁷ cannot both be hydrogen;-   W is hydrogen, C₁₋₄alkyl, C(═O)X, or P(═O)(OY)(OZ);-   X is C₁₋₆alkyl, NR⁸R⁹, N(R⁸)CH₂(CH₂)_(n)C(═O)N(R⁸)(R⁹), OC₁₋₆alkyl,    C₁₋₆alkyl (which can be substituted with halogen, hydroxyl,    CO₂C₁₋₄alkyl, CON(C₁₋₄alkyl)₂, C(═NH)NH₂, NHC(═NH)NH₂, NH₂),    C₂₋₄alkenyl (substituted by phenyl, unsubstituted or substituted    with one or more of C₁₋₄alkyl, C₁₋₄alkoxy or halogen);-   Y and Z are independently chosen from hydrogen, C₁₋₁₀ alkyl or Y and    Z can together form a lower alkyl chain of (CH₂)_(m);-   m is 2–4;-   n is 1 or 2;-   and pharmaceutically acceptable salts and solvates of the compounds    of Formula I.

Compounds that are novel and which are useful according to the presentinvention can be defined as follows:

-   wherein R¹ to R⁴ are independently chosen from hydrogen, halogen,    C₁₋₆alkyl, trifluoromethyl, O—W, C₁₋₆alkylthio, C₁₋₆alkylsulfoxyl,    C₁₋₆alkylsulfonyl, or cyano;-   R⁵ can be halogen, trifluoromethyl, cyano, NR¹⁰R¹¹;-   R⁶ and R⁷ are independently chosen from hydrogen, C₁₋₄alkyl or R⁶,    R⁷ and the carbon atom to which they are attached can form a    cyclopropyl ring, or furthermore, R⁷ and R⁸ together can be    (CH₂)_(m) to form a saturated heterocycle;-   R⁸ and R⁹ are independently chosen from hydrogen or C₁₋₄alkyl;-   R¹⁰ and R¹¹ are independently chosen from hydrogen or C₁₋₄alkyl, or    R¹⁰, R¹¹ and the nitrogen atom to which they are attached can form a    saturated heterocyclic ring selected from pyrrolidine, piperidine,    piperazine, or morpholine;-   R¹ to R⁴ cannot simultaneously be hydrogen;-   R⁶ and R⁷ cannot both be hydrogen;-   W is hydrogen, C₁₋₄alkyl, C(═O)X, or P(═O)(OY)(OZ);-   X is C₁₋₆alkyl, NR⁸R⁹, N(R⁸)CH₂(CH₂)_(n)C(═O)N(R⁸)(R⁹), OC₁₋₆alkyl,    C₁₋₆alkyl (which can be substituted with halogen, hydroxyl,    CO₂C₁₋₄alkyl, CON(C₁₋₄alkyl)₂, C(═NH)NH₂, NHC(═NH)NH₂, NH₂),    C₂₋₄alkenyl (substituted by phenyl, unsubstituted or substituted    with one or more of C₁₋₄alkyl, C₁₋₄alkoxy or halogen);-   Y and Z are independently chosen from hydrogen, C₁₋₁₀ alkyl or Y and    Z can together form a lower alkyl chain of (CH₂)_(m);-   m is 3 or 4;-   n is 1 or 2;-   and pharmaceutically acceptable salts and solvates of the compounds    of Formula I.    Preferred Compounds are:-   R¹ and R² are independently chosen from hydrogen, halogen,    C₁₋₆alkyl, trifluoromethyl, O—W, C₁₋₆alkylthio, C₁₋₆alkylsulfoxyl,    C₁₋₆alkylsulfonyl, or cyano;-   R³ and R⁴ are independently chosen from hydrogen, halogen,    C₁₋₆alkyl, trifluoromethyl, or cyano;-   R⁵ can be hydrogen, C₁₋₄alkyl, halogen, trifluoromethyl, or    C₁₋₄alkoxy;-   R⁶ and R⁷ are independently chosen from hydrogen or C₁₋₄alkyl, or    R⁶, R⁷ and the carbon atom to which they are attached can form a    cyclopropyl ring, or furthermore, R⁷ and R⁸ together can be    (CH₂)_(m) to form a saturated heterocycle;-   R⁸ and R⁹ are independently chosen from hydrogen or C₁₋₄alkyl;-   R¹ to R⁴ cannot simultaneously be hydrogen;-   R⁶ and R⁷ cannot both be hydrogen;-   W is hydrogen, C₁₋₆alkyl, C(═O)X, or P(═O)(OY)(OZ), X is C₁₋₆alkyl,    NR⁸R⁹, N(R⁸)CH₂(CH₂)_(n)C(═O)NR⁸R⁹, OC₁₋₆alkyl, C₁₋₆alkyl (which can    be substituted with halogen, hydroxyl, CO₂C₁₋₄alkyl,    CON(C₁₋₄alkyl)₂, C(═NH)NH₂, NHC(═NH)NH₂, NH₂), C₂₋₄alkenyl    (substituted by phenyl, unsubstituted or substituted with one or    more of C₁₋₄alkyl, C₁₋₄alkoxy or halogen);-   Y and Z are independently chosen from hydrogen, C₁₋₁₀alkyl or Y and    Z can together form a lower alkyl chain of (CH₂)_(m);-   m is 3;-   n is 1 or 2;    The More Preferred Compounds are:-   where R¹, R³, and R⁴ are independently chosen from hydrogen,    halogen, C₁₋₆alkyl, trifluoromethyl, or cyano;-   R² is chosen from O—W;-   R⁵ can be hydrogen, C₁₋₆alkyl, halogen, trifluoromethyl, or    C₁₋₄alkoxy;-   R⁶ is hydrogen and R⁷ is methyl;-   R⁸ and R⁹ are independently chosen from hydrogen or C₁₋₄alkyl;-   W is hydrogen, C₁₋₄alkyl, or C(═O)X;-   X is C₁₋₆alkyl, NR⁸R⁹, or N(R⁸)CH₂(CH₂)_(n)C(═O)N(R⁸)(R⁹);-   n is 1 or 2;    The Most Preferred Compounds are:-   where R¹, R³, and R⁴ are independently chosen from hydrogen or    halogen;-   R² is O—W;-   R⁵ is hydrogen or C₁₋₆alkyl;-   R⁶ is hydrogen and R⁷ is methyl;-   R⁸ and R⁹ are hydrogen;-   W is hydrogen, C₁₋₄alkyl;

It is recognized that compounds of Formula I can contain one or morechiral centers. This invention contemplates all enantiomers,diastereomers and, mixtures thereof.

In the above definitions, the total number of carbon atoms in asubstituent group is indicated by the C_(i-j) prefix where the numbers iand j define the number of carbon atoms; this definition includesstraight chain, branched chain, and cyclic alkyl or (cyclic alkyl)alkylgroups.

It is important to recognize that a substituent may be present eithersingly or multiply when incorporated into the indicated structural unit.For example, the substituent halogen, which means fluorine, chlorine,bromine, or iodine, would indicate that the unit to which it is attachedmay be substituted with one or more halogen atoms, which may be the sameor different.

Synthesis

The compounds of Formula I can be prepared by processes analogous tothose known in the art. The preparation of compounds of Formula Iwherein R² is OH and R¹ and R³–R⁵ are as defined above can be preparedfrom the appropriate O-protected substituted-indazol-6-ol (1), suitableO-protective groups are e.g. methyl or benzyl, and can be prepared bymethods well known in the art and described in Scheme 1 [U.S. Pat. No.5,494,928 (1997), WO98/30548 (1998)]. Alkylation of indazole 1 with thedesired epoxide, e.g. propylene oxide, provides the intermediate alcohol2. Alternately, it can be advantageous for certain compounds to alkylate1 using chloroacetone followed by reduction, e.g. with NaBH₄, of theintermediate ketone to obtain the intermediate 2.

The indazoles 1 can be prepared by conducting suitable functional grouptransformations on indazoles that are commercially available or that canbe prepared according to literature procedures, generally starting fromeither the desired alkoxy-2-aminophenyl ketone (5), or the suitablysubstituted alkoxy-2-fluorophenyl ketone (6), depending on availabilityof suitable precursors (Scheme 2) [J. Heterocycl. Chem. 35, 895 (1998);J. Med. Chem. 40, 2706 (1997); Comp. Heterocycl. Chem. II, Vol. 3, 1(1996)]. Also, certain indazoles 1 can be prepared from other indazoles1 by direct substitution or by selective functional grouptransformations well known to the art.

Intermediates 2 of Scheme 1 can also be prepared from the suitablysubstituted alkoxy-2-fluorophenyl ketones, for example by reaction of 6with 1-hydrazino-2-propanol [J. Amer. Chem. Soc. 76, 1283 (1954)] usingprocedures analogous to those known in the art [J. Med. Chem. 41, 5429(1998)].

The compounds of Formula I wherein R² is OC(═O)X can be prepared byprocedures analogous to those known in the art. For example, when thesubstituent OC(C═O)X is compatible with the subsequent reactionconditions as described above, such compounds can be prepared asdescribed in Schemes 1 and 2. Alternately, and preferably, compounds ofFormula I wherein R² is OC(═O)X can be prepared by reacting theappropriate indazole 7, or preferably a suitable amino-protectedintermediate, e.g. 8 (Scheme 3) with the desired activated acidderivative, such as an acid halide or active ester, or the like, toprovide, for example, the esters 9. Removal of the N-protective groupfrom the intermediate 9 provides the desired compounds 10 of Formula I.

The indazole derivatives of interest for use as starting materials forthe preparation of compounds 10 can be prepared by methods describedabove and in Scheme 1.

The compounds of this invention, Formula I, can be incorporated intovarious types of ophthalmic formulations for delivery to the eye (e.g.,topically, intracamerally, or via an implant). The compounds arepreferably incorporated into topical ophthalmic formulations fordelivery to the eye. The compounds may be combined withophthalmologically acceptable preservatives, surfactants, viscosityenhancers, penetration enhancers, buffers, sodium chloride, and water toform an aqueous, sterile ophthalmic suspension or solution. Ophthalmicsolution formulations may be prepared by dissolving a compound in aphysiologically acceptable isotonic aqueous buffer. Further, theophthalmic solution may include an ophthalmologically acceptablesurfactant to assist in dissolving the compound. Furthermore, theophthalmic solution may contain an agent to increase viscosity, such as,hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, orthe like, to improve the retention of the formulation in theconjunctival sac. Gelling agents can also be used, including, but notlimited to, gellan and xanthan gum. In order to prepare sterileophthalmic ointment formulations, the active ingredient is combined witha preservative in an appropriate vehicle, such as, mineral oil, liquidlanolin, or white petrolatum. Sterile ophthalmic gel formulations may beprepared by suspending the active ingredient in a hydrophilic baseprepared from the combination of, for example, carbopol-974, or thelike, according to the published formulations for analogous ophthalmicpreparations; preservatives and tonicity agents can be incorporated.

The compounds are preferably formulated as topical ophthalmicsuspensions or solutions, with a pH of about 5 to 8. The compounds willnormally be contained in these formulations in an amount 0.01% to 5% byweight, but preferably in an amount of 0.25% to 2% by weight. Thus, fortopical presentation 1 to 2 drops of these formulations would bedelivered to the surface of the eye 1 to 4 times per day according tothe discretion of a skilled clinician.

The compounds can also be used in combination with other agents fortreating glaucoma, such as, but not limited to, β-blockers (e.g.,timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol),carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), α₁antagonists (e.g. nipradolol), α₂ agonists (e.g., iopidine andbrimonidine), miotics (e.g., pilocarpine and epinephrine), prostaglandinanalogs (e.g., latanoprost, travaprost, unoprostone, and compounds setforth in U.S. Pat. Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444,“hypotensive lipids” (e.g., lumigan and compounds set forth in U.S. Pat.No. 5,352,708), and neuroprotectants (e.g., compounds from U.S. Pat. No.4,690,931, particularly eliprodil and R-eliprodil, as set forth in apending application U.S. Ser. No. 06/203,350, and appropriate compoundsfrom WO94/13275, including memantine.

The following examples are given to illustrate the preparation ofcompounds that are the subject of this invention but should not beconstrued as implying any limitations to the claims. The preferredcompounds of Formula I are described in Examples 2, 5 and 7. The mostpreferred is the compound of Example 2. The proton magnetic resonancespectrum of each compound of the Examples was consistent with theassigned structure.

Method 1 5-HT₂ Receptor Binding Assay

In order to determine the relative affinities of serotonergic compoundsat the 5-HT₂ receptors, their ability to compete for the binding of theagonist radioligand [¹²⁵I]DOI to brain 5-HT₂ receptors is determined asdescribed below with minor modification of the literature procedure[Neuropharmacology, 26, 1803 (1987)]. Aliquots of post mortem rat orhuman cerebral cortex homogenates (400 μl) dispersed in 50 mM TrisHClbuffer (pH 7.4) are incubated with [¹²⁵I]DOI (80 pM final) in theabsence or presence of methiothepin (10 μM final) to define total andnon-specific binding, respectively, in a total volume of 0.5 ml. Theassay mixture is incubated for 1 hour at 23° C. in polypropylene tubesand the assays terminated by rapid vacuum filtration over Whatman GF/Bglass fiber filters previously soaked in 0.3% polyethyleneimine usingice-cold buffer. Test compounds (at different concentrations) aresubstituted for methiothepin. Filter-bound radioactivity is determinedby scintillation spectrometry on a beta counter. The data are analyzedusing a non-linear, iterative curve-fitting computer program [TrendsPharmacol. Sci., 16, 413 (1995)] to determine the compound affinityparameter. The concentration of the compound needed to inhibit the[¹²⁵I]DOI binding by 50% of the maximum is termed the IC₅₀ value. Acompound is considered to possess high affinity for the 5-HT₂ receptorif the IC₅₀ value is less than 50 nM.

Method 2 5-HT₂ Functional Assay: Phosphoinositide (PI) Turnover Assay

The relative agonist activity of serotonergic compounds at the 5-HT₂receptor can be determined in vitro using the ability of the compoundsto stimulate the production of [³H]inositol phosphates in[³H]myo-inositol-labeled A7r5 rat vascular smooth muscle cells by theirability to activate the enzyme phospholipase C. These cells are grown inculture plates, maintained in a humidified atmosphere of 5% CO₂ and 95%air and fed semi-weekly with Dulbecco's modified Eagle medium (DMEM)containing 4.5 g/l glucose and supplemented with 2 mM glutamine, 10μg/ml gentamicin, and 10% fetal bovine serum. For the purpose ofconducting the phosphoinositide (PI) turnover experiments, the A7r5cells are cultured in 24-well plates as previously [J. Pharmacol. Expt.Ther., 286, 411 (1998)]. Confluent cells are exposed for 24–30 hrs to1.5 μCi [³H]-myo-inositol (18.3 Ci/mmol) in 0.5 ml of serum-free medium.Cells are then rinsed once with DMEM/F-12 containing 10 mM LiCl prior toincubation with the test agent (or solvent as the control) in 1.0 ml ofthe same medium for 1 hr at 37° C., after which the medium is aspiratedand 1 ml of cold 0.1 M formic acid added to stop the reaction. Thechromatographic separation of [3H]-inositol phosphates ([³H]-IPs) on anAG-1-X8 column is performed as previously described [J. Pharmacol. Expt.Ther. 286, 411 (1998)] with sequential washes with H₂O and 50 mMammonium formate, followed by elution of the total [³H]-IPs fractionwith 1.2 M ammonium formate containing 0.1 M formic acid. The eluate (4ml) is collected, mixed with 15 ml scintillation fluid, and the total[³H]-IPs determined by scintillation counting on a beta-counter.Concentration-response data are analyzed by the sigmoidal fit functionof the Origin Scientific Graphics software (Microcal Software,Northampton, Mass.) to determine agonist potency (EC₅₀ value) andefficacy (E_(max)). Serotonin (5-HT) is used as a positive control(standard) agonist compound and the efficacy of test compounds iscompared to that of 5-HT (set at 100%). The concentration of thecompound needed to stimulate the production of [³H]-IPs by 50% of themaximum response is termed the EC₅₀ value. Compounds are consideredpotent agonists if their EC₅₀ values in this functional assay are ≦1 μMand are considered full agonists if their efficacy is >80% of that of5-HT.

The above procedures were used to generate the data shown in Table 1.

TABLE 1 5-HT₂ Receptor Binding and Functional Data. Efficacy CompoundIC₅₀, nM EC₅₀, nM (E_(max), %) α-Methylserotonin 3.5 189 104 Example 13.1 578 71 Example 2 3.0 483 87 Example 4 — 243 73 Example 5 2.0 541 64Example 6 2.2 1050 84

EXAMPLE 1 2-(6-Methoxy-3-methyl-indazol-1-yl)-1-methylethylamineFumarate Step A: 6-Methoxy-3-methyl-1H-indazole

To a solution of 2-fluoro-4-methoxyacetophenone (1.90 g, 11.3 mmol) inethanol (20 ml) was added hydrazine hydrate (1.4 ml, 45.0 mmol) andheated at reflux temperature for 6 h. This mixture was evaporated to aresidue and ethylene glycol (10 ml) was added. The mixture was heated at150° C. for 18 h, cooled to room temperature, diluted with water (50ml), and extracted with dichloromethane (3×60 ml). The combined extractswere washed with brine (10 ml), dried (MgSO₄) and evaporated to aresidue, which was crystallized from ethyl acetate to give a solid (1.1g, 59%): MS(ES) m/z 163 (M⁺).

Step B: 1-(6-Methoxy-3-methyl-indazol-1-yl)-propan-2-one

To a solution of the product from Step A (1.1 g, 6.7 mmol) in DMF (10ml) was added sodium hydride (60% in oil, 0.41 g, 10.2 mmol) at roomtemperature. After stirring for 30 min, chloroacetone (0.79 ml, 10.2mmol) was added, and the solution heated at 60° C. for 6 h. The reactionmixture was diluted with a saturated aqueous solution of ammoniumchloride (10 ml) and extracted with ethyl acetate (3×65 ml). Thecombined extracts were washed with brine (10 ml), dried (MgSO₄), andevaporated to give a residue which was purified by chromatography(silica, 20% to 30% ethyl acetate in hexane) to give an oil (1.3 g,88%): MS (ES) m/z 219 (M⁺).

Step C: 1-(6-Methoxy-3-methyl-indazol-1-yl)-propan-2-ol

Sodium borohydride (0.21 g, 5.5 mmol) was added to a solution of theproduct from Step B (1.2 g, 5.5 mmol) in MeOH (10 ml) at roomtemperature. After stirring for 2 h at room temperature the solvent wasevaporated and a saturated aqueous solution of ammonium chloride (10 mL)was added to the residue; this mixture was extracted with ethyl acetate(3×50 mL). The combined extracts were washed with brine (10 ml), dried(MgSO₄) and evaporated to a residue which was purified by chromatography(silica, 20% to 30% ethyl acetate in hexane) to give an oil (0.68 g,56%): MS (ES) m/z 221 (M⁺).

Step D: 1-(2-Azido-propyl)-6-methoxy-3-methyl-1H-indazole

To a solution of the product from Step C (0.66 g, 3.0 mmol) indichloromethane (10 ml) at 0° C. was added triethylamine (0.55 ml, 3.9mmol) and methanesulfonyl chloride (0.31 ml, 3.9 mmol). After stirringfor 30 min, ether (50 ml) and water (50 ml) were added. The organiclayer was separated and the aqueous extracted with ether (2×50 ml). Thecombined ether extracts were washed with brine (30 ml), dried (MgSO₄),and evaporated. The residue was taken up in DMF (6 ml) and sodium azide(0.26 g, 3.9 mmol) added. This mixture was heated at 70° C. for 12 h,poured into water, and extracted with ether (3×50 ml). The combinedextracts were washed with brine, dried (MgSO₄), and evaporated to aresidue, which was purified by chromatography (silica, hexane to 10%ethyl acetate in hexane) to give an oil (0.51 g, 69%): MS (ES) m/z 246(M⁺).

Step E: 2-(6-Methoxy-3-methyl-indazol-1-yl)-1-methylethylamine Fumarate

To a solution of the product from Step D (0.50 g, 2.0 mmol) in methanolat room temperature was added palladium-on-carbon (10%, 0.10 g). Thissuspension was stirred for 18 h under an atmosphere of hydrogen. Thereaction mixture was filtered through a filter aid and the filtrateevaporated to a residue (0.43 g, 96%) which was converted to the fumaricacid salt and crystallized from methanol/ether to give a colorless solid(0.27 g): mp 150–152° C.; MS (ES) m/z 191 (M⁺). Analysis. Calculated forC₁₂H₁₇N₃O.1.0 C₄H₄O₄.1.0 CH₃OH: C, 55.58; H, 6.86; N, 11.44. Found: C,55.41; H, 6.85; N, 11.37.

EXAMPLE 2 1-(2-Aminopropyl)-3-methyl-1H-indazol-6-ol Fumarate Step A:1-(4-Benzyloxy-2-fluoro-phenyl)-ethanone

Potassium carbonate (5.5 g, 40.0 mmol) and benzyl bromide (4.6 ml, 38.9mmol) were added to a solution of 2-fluoro-4-hydroxyacetophenone (5.0 g,32.4 mmol) in ethanol (50 ml), and the mixture was heated at refluxtemperature for 16 h. The reaction mixture was evaporated to a residueto which 2 N HCl (100 ml) was added. This mixture was extracted withethyl ether (3×60 ml) and the combined extracts were washed with brine(10 ml), dried (MgSO₄), and evaporated to a residue, which wascrystallized from ethyl acetate (7.4 g, 93%): MS(ES) m/z 245 (M⁺).

Step B: 6-Benzyloxy-3-methyl-1H-indazole

A solution of the product from Step A (7.4 g, 30.3 mmol) in ethanol (20mL) was treated as described for Example 1, Step A to give a colorlesssolid (6.1 g, 69%): MS(ES) m/z 239 (M⁺).

Step C: 1-(6-Benzyloxy-3-methyl-indazol-1-yl)-propan-2-one

A solution of the product from Step B (2.3 g, 9.7 mmol) in DMF (10 ml)was treated by the sequence described for Example 1, Step B to give aresidue, which was used in the next step without further purification:MS (ES) m/z 295 (M⁺).

Step D: 1-(6-Benzyloxy-3-methyl-indazol-1-yl)-propan-2-ol

A solution of the product from Step C (3.3 g, 5.5 mmol) in MeOH (10 ml)was treated as described for Example 1, Step C to give an oil (0.30 g,10%): MS (ES) m/z 297 (M⁺).

Step E: 1-(2-Azido-propyl)-6-benzyloxy-3-methyl-1H-indazole

A solution of the product from Step D (0.28 g, 0.95 mmol) indichloromethane (10 ml) was treated by the sequence described forExample 1, Step D to give an oil (0.16 g, 52%): MS (ES) m/z 322 (M⁺).

Step F: 1-(2-Aminopropyl)-3-methyl-1H-indazol-6-ol Fumarate

A solution of the product from Step E (0.16 g, 0.50 mmol) in methanolwas treated as described for Example 1, Step E to give a residue (0.10g, 97%) which was converted to fumaric acid salt and crystallized from amixture of methanol and ether to give a colorless solid (0.11 g):mp:166–168° C.; MS(ES) m/z 206 (M⁺). Analysis. Calculated forC₁₁H₁₅N₃₀.1.8 C₄H₄O₄: C, 52.78; H, 5.40; N, 10.15. Found: C, 52.45; H,5.53; N, 10.29.

EXAMPLE 3 2,2-Dimethyl-propionic Acid 1-(2-aminopropyl)-1H-indazol-6-ylEster Fumarate Step A: 2,2-Dimethyl-propionic acid 1H-indazol-6-yl Ester

To a solution of 1H-indazol-6-ol (0.88 g, 6.6 mmol) in dichloromethane(10 ml) at room temperature was added triethylamine (0.98 ml, 7.0 mmol)and DMAP (0.05 g) followed by trimethylacetyl chloride (0.82 ml, 6.6mmol). After stirring for 1 h, the mixture was diluted with saturatedaqueous solution of ammonium chloride (20 ml) and extracted with ethylacetate (3×50 ml). The combined extracts were washed with brine (10 ml),dried (MgSO₄), and evaporated to a residue which was purified bychromatography (silica, 10% to 20% ethyl acetate in hexane) to give anoil (1.1 g, 76%): ¹H NMR (CDCl₃) δ 8.15 (d, J=0.8 Hz, 1H), 8.01 (s, 1H),7.75 (s, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.01 and 6.96 (dd, J=2.0 and 8.6Hz, 1H), 1.59 (s, 9H); MS(ES) m/z 219 (M⁺).

Step B: 2,2-Dimethyl-propionic Acid 1-(2-oxo-propyl)1H-indazol-6-ylEster

A solution of the product of Step A (1.5 g, 6.9 mmol) in DMF (10 ml) wastreated by the procedure described for Example 1, Step B to give an oil(1.3 g, 62%): ¹H NMR (CDCl₃) δ 8.09 (d, J=0.8 Hz, 1H), 7.99 (s, 1H),7.90 (s, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.01 and 6.96 (dd, J=2.0 and 8.6Hz, 1H), 4.64 (s, 2H), 2.15 (s, 3H), 1.56 (s, 3H) 1.27 (s, 6H); MS(ES)m/z 275 (M⁺).

Step C: 2,2-Dimethyl-propionic Acid 1-(2-hydroxy-propyl)-1H-indazol-6-ylEster

A solution of the product of Step B (0.91 g, 3.6 mmol) in methanol (10ml) was treated by the procedure described for Example 1, Step C to givean oil (0.79 g, 86%) that was used in the next reaction with furtherpurification: ¹H NMR δ (CDCl₃) 7.99 (s, 1H), 7.98 (s, 1H), 7.60 (d,J=8.6 Hz, 1H), 7.01 and 6.96 (dd, J=2.0 and 8.6 Hz, 1H,), 4.14–3.89 (m,3H), 1.56 (s, 3H) 1.32 (s, 9H).

Step D: 2,2-Dimethyl-propionic Acid 1-(2-azido-propyl)-1H-indazol-6-ylEster

A solution of the product from Step C (1.70 g, 6.2 mmol) indichloromethane (10 ml) was treated by the procedure described forExample 1, Step D to give an oil (1.30 g, 69%): MS(ES) m/z 274 (M⁺−28).

Step E: 2,2-Dimethyl-propionic Acid 1-(2-aminopropyl)-1H-indazol-6-ylEster Fumarate

A solution of the Product from Step D (1.25 g, 4.1 mmol) in methanol wastreated by the procedure described for Example 1, Step E to give an oil(0.13 g, 88%) which was treated with fumaric acid; the salt which formedwas crystallized from a mixture of methanol and ether to give acolorless solid: mp180–182° C.; 1H NMR (DMSO-d₆) δ 8.37 (s, 1H), 7.89(s, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.45 (s, 2H),4.18 –4.01 (m, 2H), 3.5 (m, 1H), 1.50 (s, 9H) 1.30 (d, J=6.6 Hz, 3H);MS(ES) m/z 276 (M⁺). Analysis. Calculated for C₁₅H₂₁N₃O₂.1.2 C₄H₄O₄: C,57.36; H, 6.27; N, 10.13. Found: C, 56.98; H, 6.57; N, 10.22.

EXAMPLE 4 2-(6-Methoxy-indazol-1-yl)-1-methyl-ethylamine Step A:[2-(6-Hydroxy-indazol-1-yl)-1-methyl-ethyl]-carbamic Acid Benzyl Ester

To a solution of 1-(2-aminopropyl)-indazol-6-ol (0.46 g, 2.4 mmol) inTHF (10.0 mL) was added a saturated aqueous solution of sodiumbicarbonate (2.0 mL) followed by benzyl chloroformate (0.40 mL) at roomtemperature. After stirring for 1 h, the solution was diluted with 1 NHCl (10 mL) and ammonium chloride (20 mL) followed by extraction withethyl acetate (3×50 mL). The combined extracts were washed with brine(10 mL), dried (MgSO₄) and evaporated to give a residue which was usedin the next step without further purification (0.75 g, 98%); MS (ES) m/z326 (M⁺).

Step B: [2-(6-Methoxy-indazol-1-yl)-1-methyl-ethyl]-carbamic Acid BenzylEster

To a solution of the product from Step A (0.95 g, 3.19 mmol) in DMF (10mL) was added cesium carbonate (1.26 g, 3.70 mmol) followed byiodomethane (0.23 mL, 3.70 mmol) at room temperature. After stirring for3 h, saturated aqueous ammonium chloride (30 mL) was added and themixture extracted with ethyl acetate (3×65 mL). The combined extractswere washed with brine (10 mL), dried (MgSO₄) and evaporated to aresidue which was purified by chromatography (silica, 20% ethyl acetatein hexane to 30% ethyl acetate in hexane) to give a syrup (0.63 g, 92%):MS (ES) m/z 340(M⁺).

Step C: 2-(6-Methoxy-indazol-1-yl)-1-methyl-ethylamine

To a solution of the product from Step B (0.68 g, 2.0 mmol) in methanolwas added Pd/C (10%, 0.10 g) under a nitrogen atmosphere at roomtemperature. The mixture was stirred for 20 h under a hydrogenatmosphere and filtered through a filter aid. The filtrate wasevaporated to a residue which was purified by chromatography (silica, 5%methanol in dichloromethane to 10% methanol in dichloromethane) to givea syrup (0.40 g, 97%). Treatment of the syrup with fumaric acid gave aresidue that was recrystallized from methanol/ether to provide acolorless solid: mp 151–152° C.; MS (ES) m/z 206 (M⁺). Analysis.Calculated for C₁₁H₁₅N₃O.1.0 C₄H₄O₄. 1.0H₂O: C, 53.09; H, 6.24; N,12.38. Found: C, 52.88; H, 6.31; N, 12.14.

EXAMPLE 5 2-(3-Chloro-6-methoxy-indazol-1-yl)-1-methyl-ethylamine StepA: 2-Hydrazino-4-methoxy-benzoic Acid

A suspension of 2-acetylamino-4-methoxy-benzoic acid (15 g, 73.7 mmol)in water (75 mL) was cooled to −5° C. and conc HCl (150 mL) was addedfollowed by cooling to −5°. To this mixture was added a solution ofNaNO₂ (5.43 g, 77.4 mmol) in water (50 mL) that had been cooled to −5°;this solution was added at such a rate so as to maintain the temperatureof the reaction mixture between −5° and 0° C. The reaction mixture wasstirred for 10 min and the clear solution was added to a solution ofstannous chloride (41.9 g, 221 mmol) in conc HCl (150 mL) that had beencooled to −20° C. This addition was conducted so as to maintain atemperature of −20° to −10° C. for the reaction mixture, followed bystirring the mixture for 1.5 h at −20° C. The solid that formed wascollected by filtration, washed with chilled EtOH, and dried to give anoff-white solid (10.8 g): APCl/LCMS m/z 183 (M+H)⁺.

Step B: 6-Methoxy-1H-indazol-3-ol

A mixture of the product from Step A (10.5 g, 48 mmol), water (250 mL),and conc HCl (2.5 mL) was refluxed for 30 min. The volume of thereaction mixture was reduced by evaporation (ca 100 mL) and the pHadjusted to 7 by the slow addition of a saturated aqueous solution ofsodium carbonate at room temperature. The solid that formed uponstanding was collected and dried to give a gray solid (6.8 g): APCl/LCMSm/z 165 (M+H)⁺.

Step C: 3-Chloro-6-methoxy-1H-indazole

To a solution of the product from Step B (1 g, 6.1 mmol) in pyridine(0.5 mL, 6.1 mmol) was added phosphorous oxychloride (0.9 mL, 9.2 mmol)and the mixture heated at 130–140° C. for 5 h. The reaction mixture wascooled to 70° C. and poured onto ice (100 g). After standing for 24 h,the solid was collected and dried to give a cream-colored solid (0.42g): ES/LCMS m/z 181 (M−H)⁺.

Step D: [2-(3-Chloro-6-methoxy-indazol-1-yl)-1-methyl-ethyl]-carbamicAcid Benzyl Ester

To a solution of the product from Step C (0.18 g, 1 mmol) and (2-bromo-1methyl-ethyl)-carbamic acid benzyl ester (0.27 g, 1 mmol) in DMF (2 mL)was added potassium carbonate (0.17 g, 1.2 mmol) and the mixture stirredat 75° for 18 h. Ethyl acetate (20 mL) and water (20 mL) were added tothe reaction mixture and the aqueous layer was separated and extractedwith ethyl acetate (3×20 mL). The combined extracts were washed withbrine (30 mL), dried (MgSO₄), and evaporated to a residue that waspurified by chromatography (silica, hexane to 15% ethyl acetate inhexane) to give a syrup (0.27 g): APCl/LCMS m/z 374 (M+H)⁺.

Step E: 2-(3-Chloro-6-methoxy-indazol-1-yl)-1-methyl-ethylamine

To a solution of the product from Step D (0.15 g, 0.4 mmol) in1,2-dichloroethane (4 mL) under nitrogen was added borontribromide-dimethylsulfide complex (2.4 mmol, 2.4 mL of a 1 N solutionin 1,2-dichloroethane) and the mixture was heated at 84° C. for 3 h.After cooling, saturated aqueous sodium bicarbonate (5 mL) was added andthe mixture was extracted with chloroform (3×10 mL). The combinedextracts were washed with brine (10 mL), dried (MgSO₄), and purified bychromatography (C-18 RP-HPLC, 5% acetonitrile/water to 70%acetonitrile/water containing 0.1% trifluoroacetic acid) to give aresidue (0.03 g) that was converted to the dihydrochloride salt:ESI/LCMS m/z 240 (M+H)⁺.

EXAMPLE 6 1-(2-Aminopropyl)-3-chloro-1H-indazol-6-ol

A solution of the product from Example 5, Step D (0.1 g, 0.27 mmol) wastreated as described in Step E of Example 5 but the reaction mixture washeated for 8 h to give a syrup (0.015 g), which was converted to thedihydrochloride salt: ESI/LCMS m/z 226 (M+H)⁺.

Ingredients Amount (wt %) 1-(2-Aminopropyl)-3-methyl-1H-indazol- 0.01–2%6-ol fumarate Hydroxypropyl methylcellulose 0.5%  Dibasic sodiumphosphate (anhydrous) 0.2%  Sodium chloride 0.5%  Disodium EDTA (Edetatedisodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodiumhydroxide/Hydrochloric acid For adjusting pH to 7.4 Purified water q.s.to 100%

Ingredients Amount (wt %) 1-(2-Aminopropyl)-3-methyl-1H- 0.01–2%indazol-6-ol fumarate Methyl cellulose 4.0%  Dibasic sodium phosphate(anhydrous) 0.2%  Sodium chloride 0.5%  Disodium EDTA (Edetate disodium)0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodiumhydroxide/Hydrochloric acid For adjusting pH to 7.4 Purified water q.s.to 100%

Ingredients Amount (wt %) 1-(2-Aminopropyl)-3-methyl-1H- 0.01–2%indazol-6-ol fumarate Guar gum   0.4–6.0% Dibasic sodium phosphate(anhydrous) 0.2%– Sodium chloride 0.5%  Disodium EDTA (Edetate disodium)0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodiumhydroxide/Hydrochloric acid For adjusting pH Purified water q.s. to 100%

Ingredients Amount (wt %) 1-(2-Aminopropyl)-3-methyl-1H-indazol-6-ol0.01–2% fumarate White petrolatum and mineral oil and lanolin Ointmentconsistency Dibasic sodium phosphate (anhydrous) 0.2%  Sodium chloride0.5%  Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05%Benzalkonium chloride 0.01% Sodium hydroxide/Hydrochloric acid Foradjusting pH

1. A compound of the formula:

wherein R¹ to R⁴ are independently chosen from hydrogen, halogen, C₁₋₆alkyl, trifluoromethyl, O—W, C₁₋₆ alkylthio, C₁₋₆ alkylsulfoxyl, C₁₋₆alkylsulfonyl, or cyano; R⁵ is halogen, trifluoromethyl, cyano, orNR¹⁰R¹¹; R⁶ and R⁷ are independently chosen from hydrogen, C₁₋₄ alkyl orR⁶, R⁷ and the carbon atom to which they are attached form a cyclopropylring, or furthermore, R⁷ and R⁸ together are (CH₂)_(m) to form asaturated heterocycle; R⁸ and R⁹ are independently chosen from hydrogenor C₁₋₄ alkyl; R¹⁰ and R¹¹ are independently chosen from hydrogen orC₁₋₄ alkyl, or R¹⁰, R¹¹ and the nitrogen atom to which they are attachedform a saturated heterocyclic ring selected from pyrrolidine,piperidine, piperazine, or morpholine; R¹ to R⁴ are not simultaneouslyhydrogen; R⁶ and R⁷ are not both hydrogen; W is hydrogen, C₁₋₄ alkyl,C(═O)X, or P(═O)(OY)(OZ); X is C₁₋₆alkyl, NR⁸R⁹,N(R⁸)CH₂(CH₂)_(n)C(═O)N(R⁸)(R⁹), OC₁₋₆ alkyl, C₁₋₆alkyl, C₂₋₄ alkenyl,wherein said C₁₋₆ alkyl is optionally substituted with halogen,hydroxyl, CO₂C₁₋₄ alkyl, CON(C₁₋₄ alkyl)₂, C(═NH)NH₂, NHC(═NH)NH₂, orNH₂, and wherein said C₂₋₄ alkenyl is optionally substituted by phenyl,unsubstituted or substituted with one or more of C₁₋₄ alkyl, C₁₋₄ alkoxyor halogen; Y and Z are independently chosen from hydrogen, C₁₋₁₀ alkylor Y and Z together form a lower alkyl chain of (CH₂)_(m); m is 3 or 4;n is 1 or 2; and pharmaceutically acceptable salts and solvates of thecompound.
 2. The compound of claim 1 wherein: R¹ and R² areindependently chosen from hydrogen, halogen, C₁₋₆ alkyl,trifluoromethyl, O—W, C₁₋₆ alkylthio, C₁₋₆ alkylsulfoxyl, C₁₋₆alkylsulfonyl, or cyano; R³ and R⁴ are independently chosen fromhydrogen, halogen, C₁₋₆ alkyl, trifluoromethyl, or cyano; R⁵ is halogenor trifluoromethyl; R⁶ and R⁷ are independently chosen from hydrogen orC₁₋₄ alkyl, or R⁶, R⁷ and the carbon atom to which they are attachedform a cyclopropyl ring, or furthermore, R⁷ and R⁸ together are(CH₂)_(m) to form a saturated heterocycle; R⁸ and R⁹ are independentlychosen from hydrogen or C₁₋₄ alkyl; R¹ to R⁴ are not simultaneouslyhydrogen; R⁶ and R⁷ are not both hydrogen; W is hydrogen, C₁₋₆ alkyl,C(═O)X, or P(═O)(OY)(OZ), X is C₁₋₆ alkyl, NR⁸R⁹,N(R⁸)CH₂(CH₂)_(n)C(═O)NR⁸R⁹, OC₁₋₆ alkyl, C₁₋₆ alkyl, C₂₋₄ alkenyl,wherein said C₁₋₆ alkyl is optionally substituted with halogen,hydroxyl, CO₂C₁₋₄ alkyl, CON(C₁₋₄ alkyl)₂, C(═NH)NH₂, NHC(═NH)NH₂, orNH₂, and wherein said C₂₋₄ alkenyl is optionally substituted by phenyl,unsubstituted or substituted with one or more of C₁₋₄ alkyl, C₁₋₄ alkoxyor halogen; Y and Z are independently chosen from hydrogen, C₁₋₁₀ alkylor Y and Z together form a lower alkyl chain of (CH₂)_(m); m is 3; n is1 or
 2. 3. The compound of claim 1 wherein: R¹, R³, and R⁴ areindependently chosen from hydrogen, halogen, C₁₋₆ alkyl,trifluoromethyl, or cyano; R² is chosen from O—W; R⁵ is halogen ortrifluoromethyl; R⁶ is hydrogen and R⁷ is methyl; R⁸ and R⁹ areindependently chosen from hydrogen or C₁₋₄ alkyl; W is hydrogen,C₁₋₄alkyl, or C(═O)X; X is C₁₋₆ alkyl, NR⁸R⁹, orN(R⁸)CH₂(CH₂)_(n)C(═O)N(R⁸)(R⁹); n is 1 or
 2. 4. The compound of claim 1wherein: R¹, R³, and R⁴ are independently chosen from hydrogen orhalogen; R² is O—W; R⁵ is halogen or trifluoromethyl; R⁶ is hydrogen andR⁷ is methyl; R⁸ and R⁹ are hydrogen; W is hydrogen, C₁₋₄ alkyl.
 5. Thecompound of claim 1, wherein said compound is:1-(2-aminopropyl)-3-chloro-1H-indazol-6-ol fumarate or2-(3-chloro-6-methoxy-indazol-1-yl)-1-methyl-ethylamine.
 6. A topicalophthalmic composition for lowering and controlling normal or elevatedintraocular pressure and treating glaucoma, comprising apharmaceutically effective amount of a compound of claim 1, 2, 3, 4, or5 and a pharmaceutically acceptable carrier or diluent.
 7. Compositionaccording to claim 6 containing additionally one or more other agentsfor treating glaucoma.
 8. Composition according to claim 7 in which theother agent is selected from the group consisting of β-blockers,carbonic anhydrase inhibitors, α₁ antagonists, α₂ agonists, miotics,prostaglandin analogs, hypotensive lipids, and neuroprotectants. 9.Composition according to claim 7 in which the other agent is one or moreof the following: timolol, betaxolol, levobetaxolol, carteolol,levobunolol, propranolol, brinzolamide, dorzolamide, nipradolol,iopidine, brimonidine, pilocarpine, epinephrine, latanoprost,travaprost, unoprostone, lumigan, eliprodil and R-eliprodil.
 10. Amethod of controlling normal or elevated intraocular pressure ortreating glaucoma, comprising administering a pharmaceutically effectiveamount of a compound of claim 1, 2, 3, 4, or
 5. 11. A method ofcontrolling normal or elevated intraocular pressure or treating glaucomacomprising administering a pharmaceutically effective amount of acompound of the formula:

wherein R¹ to R⁴ are independently chosen from hydrogen, halogen, C₁₋₆alkyl, trifluoromethyl, O—W, C₁₋₆ alkylthio, C₁₋₆ alkylsulfoxyl, C₁₋₆alkylsulfonyl, or cyano; R⁵ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,halogen trifluoromethyl, cyano, or NR¹⁰R¹¹; R⁶ and R⁷ are independentlychosen from hydrogen, C₁₋₄ alkyl or R⁶, R⁷ and the carbon atom to whichthey are attached form a cyclopropyl ring, or furthermore, R⁷ and R⁸together are (CH₂)_(m) to form a saturated heterocycle; R⁸ and R⁹ areindependently chosen from hydrogen or C₁₋₄ alkyl; R¹⁰ and R¹¹ areindependently chosen from hydrogen or C₁₋₄ alkyl, or R¹⁰, R¹¹ and thenitrogen atom to which they are attached form a saturated heterocyclicring selected from pyrrolidine, piperidine, piperazine, or morpholine;R¹ to R⁴ are not simultaneously hydrogen; R⁶ and R⁷ are not bothhydrogen; W is hydrogen, C₁₋₄ alkyl, C(═O)X, or P(═O)(OY)(OZ); X is C₁₋₆alkyl, NR⁸R⁹, N(R⁸)CH₂(CH₂)_(n)C(═O)N(R⁸)(R⁹), OC₁₋₆ alkyl, C₁₋₆ alkyl,C₂₋₄ alkenyl, wherein said C₁₋₆ alkyl is optionally substituted withhalogen, hydroxyl, CO₂C₁₋₄ alkyl, CON(C₁₋₄ alkyl)₂, C(═NH)NH₂,NHC(═NH)NH₂, or NH₂, C₂₋₄ alkenyl and wherein said C₂₋₄ alkenyl isoptionally substituted by phenyl, unsubstituted or substituted with oneor more of C₁₋₄ alkyl, C₁₋₄ alkoxy or halogen; Y and Z are independentlychosen from hydrogen, C₁₋₁₀ alkyl or Y and Z together form a lower alkylchain of (CH₂)_(m); m is 2–4; n is 1 or 2; and pharmaceuticallyacceptable salts and solvates of the compounds.
 12. The method of claim10 or 11, wherein said compound is administered in combination with oneor more other agents for treating glaucoma.
 13. The method of claim 12in which the other agent is selected from the group consisting ofβ-blockers, carbonic anhydrase inhibitors, α₁ antagonists, α₂ agonists,miotics, prostaglandin analogs, hypotensive lipids, andneuroprotectants.
 14. The method of claim 12 in which the other agent isone or more of the following: timolol, betaxolol, levobetaxolol,carteolol, levobunolol, propranolol, brinzolamide, dorzolamide,nipradolol, iopidine, brimonidine, pilocarpine, epinephrine,latanoprost, travoprost, unoprostone, lumigan, eliprodil or R-eliprodil.